Processes and compounds for the preparation of substituted naphthylindole derivatives

ABSTRACT

The present invention provides processes for the preparation of substituted naphthylindole derivatives that can be used as inhibitors of plasminogen activator inhibitor-1 (PAI-1). In certain embodiments of the invention, the processes involve reactions that include one or more of an Oppenauer oxidation, a Fischer indole synthesis, a methyl ether cleavage, or coupling a substituted methyltetrazole with a substituted naphthol.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of application Ser. No. 11/339,802,filed Jan. 25, 2006, which claims the benefit of U.S. ProvisionalApplication No. 60/647,618, filed Jan. 27, 2005, the entire disclosureeach of which is hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to processes for the preparation ofsubstituted naphthylindole derivatives that can be used, for example, asinhibitors of plasminogen activator inhibitor-1 (PAI-1) to treat deepvein thrombosis, coronary heart disease, pulmonary fibrosis, and otherconditions resulting from fibrinolytic disorders.

BACKGROUND OF THE INVENTION

Plasminogen activator inhibitor-1 (PAI-1) is a major regulatorycomponent of the plasminogen-plasmin system. PAI-1 is the principalphysiologic inhibitor of both tissue type plasminogen activator (tPA)and urokinase type plasminogen activator (uPA). Elevated plasma levelsof PAI-1 have been associated with thrombotic events as indicated byanimal experiments (Krishnamurti, Blood, 69, 798 (1987); Reilly,Arteriosclerosis and Thrombosis, 11, 1276 (1991); Carmeliet, Journal ofClinical Investigation, 92, 2756 (1993)) and clinical studies (Rocha,Fibrinolysis, 8, 294, 1994; Aznar, Haemostasis 24, 243 (1994)). Elevatedlevels of PAI-1 have also been implicated in diseases such as polycysticovary syndrome (Nordt, Journal of clinical Endocrinology and Metabolism,85, 4, 1563 (2000)) and bone loss induced by estrogen deficiency (Daci,Journal of Bone and Mineral Research, 15, 8, 1510 (2000)). Antibodyneutralization of PAI-1 activity has been found to result in promotionof endogenous thrombolysis and reperfusion (Biemond, Circulation, 91,1175 (1995); Levi, Circulation 85, 305, (1992)). Accordingly, agentsthat inhibit PAI-1 would be of utility in treating, for example,conditions originating from fibrinolytic disorders such as deep veinthrombosis, coronary heart disease, pulmonary embolism, and polycysticovary syndrome. A need exists in the art for processes for the efficientpreparation of PAI-1 inhibitors.

SUMMARY OF THE INVENTION

This invention relates to processes for the preparation of substitutednaphthylindole derivatives that can be used as inhibitors of plasminogenactivator inhibitor-1 (PAI-1), as well as synthetic intermediates usefulin such processes.

In preferred embodiments, the invention is directed to processes thatcomprise reacting a compound of formula (3):

wherein

-   -   X is a leaving group;    -   R₇ is hydrogen, alkyl of 1 to 6 carbon atoms, alkylaryl of 7 to        20 carbon atoms, or aryl of 6 to 14 carbon atoms optionally        substituted with 1 to 3 R₈ groups;    -   R₈ is hydrogen, alkyl of 1 to 3 carbon atoms, cycloalkyl of 3 to        5 carbon atoms, —CH₂cycloalkyl of 4 to 6 carbon atoms, alkanoyl        of 2 to 4 carbon atoms, halogen, hydroxy, perfluoroalkyl of 1 to        3 carbon atoms, alkoxy of 1 to 3 carbon atoms, amino, alkylamino        of 1 to 3 carbon atoms, dialkylamino of 1 to 3 carbon atoms, or        perfluoroalkoxy of 1 to 3 carbon atoms; and    -   n is an integer from 0 to 6;

in the presence of an inorganic or organic base, with a compound offormula (2):

wherein:

-   -   R₁, R₂, R₃, and R₄ are each, independently, hydrogen, alkyl of 1        to 3 carbon atoms, cycloalkyl of 3 to 5 carbon atoms,        —CH₂cycloalkyl of 4 to 6 carbon atoms, alkanoyl of 2 to 4 carbon        atoms, halogen, hydroxyl, aryl of 6 to 14 carbon atoms        optionally substituted with 1 to 3 R₈ groups, perfluoroalkyl of        1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, amino,        alkylamino of 1 to 3 carbon atoms, dialkylamino of 1 to 3 carbon        atoms, or perfluoroalkoxy of 1 to 3 carbon atoms;    -   R₅ is hydrogen, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of        1 to 6 carbon atoms, aryl of 6 to 14 carbon atoms optionally        substituted with 1 to 3 R₈ groups, alkanoyl of 2 to 7 carbon        atoms, or aroyl of 7 to 15 carbon atoms optionally substituted        with 1 to 3 R₈ groups; and    -   R₆ is hydrogen, alkyl of 1 to 6 carbon atoms, alkylaryl of 8 to        20 carbon atoms, benzyl optionally substituted with 1 to 3 R₈        groups, alkanoyl of 2 to 7 carbon atoms, or aroyl of 7 to 15        carbon atoms optionally substituted with 1 to 3 R₈ groups;

to produce compounds of formula (1):

or pharmaceutically acceptable salts thereof.

Other embodiments of the invention relate to processes that comprisereacting a compound of formula (6):

with an alkylmagnesium halide or an arylmagnesium halide having theformula R₉MgBr and further with a hydride acceptor to produce a compoundof formula (5):

wherein

R₉ is —CH₂—R₅.

In preferred embodiments, a compound of formula (6) is reacted withhexylmagnesium bromide (HxMgBr) and further with 1-methyl-4-piperidone(MPP). Alternatively, compounds of formula (5) can be produced byreacting a compound of formula (6) consecutively with an alkyllithiumhaving the formula R₉Li, a magnesium salt, and a hydride acceptor.Preferred embodiments comprise reacting a compound of formula (6)consecutively with hexyllithium, magnesium sulfate, and1-methyl-4-piperidone (MPP).

Compounds of formula (5), in turn, can be reacted with a substitutedhydrazine having the formula

to produce compounds of formula (4):

In certain embodiments of the invention, compounds of formula (4) arereacted with an ether demethylating agent to produce compounds offormula (2) as described above.

The present invention also provides synthetic intermediates and othercompounds involved in the foregoing processes, including compounds offormulas (1), (2), (4), (5), and (6).

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Certain aspects of the present invention relate to processes for thepreparation of substituted naphthylindole derivatives that can be usedas inhibitors of plasminogen activator inhibitor-1 (PAI-1). Preferredprocesses of the invention include a direct Oppenauer oxidation on amagnesium alkoxide, allowing a ketone to be directly produced from astarting aldehyde. Further preferred embodiments of the invention relateto processes that include a Fischer indole synthesis in which anN-aryl-N-alkylhydrazine, in which the alkyl substituent is optionallysubstituted with an aryl group, is reacted with a ketone to directlyyield an N-benzylindole. The invention also encompasses processesinvolving a methyl ether cleavage in which a methoxy group is cleavedwith boron tribromide. Other embodiments of the invention relate toprocesses that involve direct coupling of protected, substitutedmethyltetrazole with naphthol. In preferred embodiments of theinvention, the tetrazole is pyran-protected.

The term “alkyl,” as used herein, refers to an aliphatic hydrocarbonchain having up to 12 carbon atoms, preferably 1 to 6 carbon atoms, andmore preferably 1 to 3 carbon atoms. The term “alkyl” includes, but isnot limited to, straight and branched chains such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl,isopentyl, neo-pentyl, n-hexyl, and isohexyl.

The term “cycloalkyl,” as used herein, refers to a saturated carbocyclicgroup containing 3 to 8 ring carbon atoms, preferably 3 to 5 ring carbonatoms. Cycloalkyl groups may be monocyclic or bicyclic, and arepreferably monocyclic.

The term “aryl,” as used herein refers to a 6 to 14 membered carbocyclicaromatic ring. Aryl groups may be monocyclic or bicyclic. Monocyclicaryl groups preferably have 6 members and bicyclic aryl groupspreferably have 10 members. Exemplary aryl groups include phenyl andnaphthyl.

The term “perfluoroalkyl,” as used herein, refers to a straight orbranched aliphatic hydrocarbon chain of 1 to 6 carbon atoms andpreferably 1 to 3 carbon atoms, in which all hydrogens are replaced withfluorine.

The term “alkanoyl,” as used herein, refers to the group R—C(═O)— whereR is an alkyl group of 1 to 6 carbon atoms, preferably 1 to 3 carbonatoms, as previously defined.

The term “alkoxy,” as used herein, refers to the group R-Q- where R isan alkyl group of 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms,as previously defined.

The term “perfluoroalkoxy,” as used herein, refers to the group R-Q-where R is a perfluoroalkyl group of 1 to 6 carbon atoms, preferably 1to 3 carbon atoms, as previously defined.

The terms “alkylamino” and “dialkylamino,” as used herein, respectivelyrefer to —NHR and —NRR_(a), where R and R_(a) are independently selectedfrom an alkyl group of 1 to 6 carbon atoms, preferably 1 to 3 carbonatoms, as previously defined.

The term “carboxy,” as used herein, refers to the group —COOH.

The terms “halogen” or “halo,” as used herein, refer to chlorine,bromine, fluorine or iodine.

The term “alkylaryl,” as used herein, refers to the group R-aryl- whereR is an alkyl group of 1 to 6 carbon atoms as previously defined, andaryl is an aryl group of 6 to 14 carbon atoms as previously defined.

The term “aroyl,” as used herein, refers to the group aryl-C(O)—, wherearyl is an aryl group of 6 to 14 carbon atoms as previously defined.

The term “alkaline earth metal,” as used herein, refers to beryllium,magnesium, calcium, strontium, barium, or radium.

The terms “inorganic base” and “organic base,” as used herein, refer tocompounds that react with an acid to form a salt; compounds that producehydroxide ions in an aqueous solution (Arrhenius bases); molecules orions that capture hydrogen ions (Bronsted-Lowry bases); and/or moleculesor ions that donate an electron pair to form a chemical bond (Lewisbases).

The term “hydride acceptor,” as used herein, refers to a chemical entityto which a hydride can be transferred from a hydride donor. The term“hydride donor,” as used herein, refers to a chemical entity that cantransfer a hydride to a hydride acceptor. Certain hydride acceptorscontain a carbonyl group. Hydride acceptors include, for example,cyclohexanone and benzaldehyde. Hydride acceptors are described, forexample, in Byrne, B., et al., Tetrahedron Letters 28:769-72 (1987);Tanikawa, S., et al., U.S. Pat. Appl. Publ. 2002198411 (2002); and Ooi,T., et al., Organic Letters 4:2669-2672 (2002).

The term “ether demethylating agent,” as used herein, refers to achemical entity that is capable of cleaving a methyl ether, asdescribed, for example, in Smith, M. B. and March, J., Advanced OrganicChemistry, Wiley 5^(th) ed. 2001, pp. 496, 503, 520, and 528. Etherdemethylating agents include, for example, BBr₃, Me₃Sil, concentratedHBr and HI, sodium N-methylanilide, and thiolate ions.

The term “leaving group,” as used herein, refers to a chemical entitythat is easily displaced from a methylenetetrazole by a nucleophile.Examples of leaving groups include, but are not limited to, halides,such as, for example, Cl, Br and I; and sulfonates, such as, forexample, mesylate, tosylate, and triflate.

Certain embodiments of the invention are directed to processes thatinvolve Oppenauer oxidation. Preferred aspects of the invention relateto Oppenauer oxidation on a magnesium alkoxide, allowing a ketone to bedirectly produced from an aldehyde. Preferred processes comprisereacting a compound of formula (6):

with an alkylmagnesium halide or an arylmagnesium halide having theformula R₉MgBr, and further with a hydride acceptor, to produce acompound of formula (5):

In preferred embodiments, the alkylmagnesium halide is hexylmagnesiumhalide, methylmagnesium halide, isobutylmagnesium halide, orbenzylmagnesium halide. In particularly preferred embodiments, thealkylmagnesium halide is hexylmagnesium bromide (HxMgBr).

Preferred hydride acceptors include optionally substituteddialkylaminobenzaldehydes and optionally substituted tertiaryaminocycloalkanones. Optional substituents for thedialkylaminobenzaldehydes and tertiary aminocycloalkanones include, butare not limited to, electron withdrawing groups such as nitro, cyano,alkoxycarbonyl, and alkylsulfonyl. In particularly preferred embodimentsof the invention, the hydride acceptor is 1-methyl-4-piperidone (MPP).Other hydride acceptors useful in the processes of the invention arefamiliar to those skilled in the art.

Other aspects of the invention relate to processes in which a compoundof formula (6) is reacted consecutively with an alkyllithium having theformula R₉Li, a magnesium salt, and a hydride acceptor to produce acompound of formula (5). In preferred processes, the alkyllithium ishexyllithium and the magnesium salt is magnesium bromide, magnesiumchloride, a magnesium sulfonate, or magnesium sulfate.

Particularly preferred processes involve magnesium alkoxide oxidation,as depicted in Scheme 1, below.

Generally, a solution of 6-methoxy-2-naphthaldehyde in toluene is addedto a solution of Grignard regent at 0° C. followed by the immediateaddition of 0.3 equivalents of 1-methyl-4-piperidone (MPP). Theresulting mixture is heated to 65° C. and treated with 1.8 equivalentsof 1-methyl-4-piperidone (MPP) over five hours. The mixture is cooled toambient temperature and quenched with 10% hydrochloric acid. The aqueouslayer is separated and the solvent in the organic layer is exchangedwith heptane to yield, upon cooling to −15° C., 80% to 90% ofcrystalline 1-(6-methoxynaphthalen-2-yl)heptan-1-one.

The reaction depicted in Scheme 1 can be performed using alternativesolvents, including hydrocarbons, such as, for example, alkanes andcycloalkanes; aromatic hydrocarbons, such as, for example, xylenes,alkylbenzenes, and alkyltoluenes; ethers, such as, for example,tert-butylmethylether, glymes, substituted furans, and dioxanes; andamides such as, for example, DMF and NMP.

In further aspects of the invention, the reaction temperatures in theprocess depicted in Scheme 1 are as much as 10° C. higher or lower thanthat indicated in the description provided above, with the exception ofthe hexyllithium addition, which typically is not carried out attemperatures higher than −5° C.

The invention also relates to processes that include a Fischer indolesynthesis. Preferred processes include a Fischer indole synthesisreaction in which a substituted hydrazine having the formula:

is reacted with a ketone to directly yield an indole. Particularlypreferred processes comprise reacting a compound of formula (5):

with a hydrazine as described herein to produce a compound of formula(4):

In certain aspects of the invention, the hydrazine is1-benzyl-1-phenylhydrazine hydrochloride (BPH),1-methyl-1-phenylhydrazine, or1-diphenylmethyl-1-(4-methoxyphenyl)hydrazine. In particularly preferredembodiments, the hydrazine is 1-benzyl-1-phenylhydrazine hydrochloride(BPH). Particularly preferred processes are those that involve thereaction depicted in Scheme 2, below.

Generally, a suspension of equimolar amounts of1-(6-methoxynaphthalen-2-yl)heptan-1-one and N-benzyl-N-phenylhydrazinehydrochloride (BPH) in ethanol is heated under reflux for five hours.Two portions of 0.1 equivalent of BPH in ethanol are added to thesuspension at one hour intervals. Alternatively, the solution of BPH inethanol is added to reaction mixture continuously. The resulting mixtureis refluxed for an hour, diluted with heptane, and treated with water at45° C. The organic and aqueous phases are separated, and the organicphase is washed with water and cooled to 10° C. to initiatecrystallization. Upon cooling to −15° C., 80%-85% of crystalline1-benzyl-2-(6-methoxy-naphthalen-2-yl)-3-pentyl-1H-indole is obtained.

The reaction depicted in Scheme 2 can be performed using alternativesolvents, including alcohols such as, for example, propanol-1 andpropanol-2; nitriles, such as, for example, acetonitrile andpropionitrile; and aromatic hydrocarbons, such as, for example, xylenes,alkylbenzenes, and alkyltoluenes.

In further embodiments of the invention, the reaction temperature in theprocess depicted in Scheme 2 is as much as 30° C. higher than thatindicated in the description provided above.

The invention further includes processes that involve methyl ethercleavage. Preferred processes are those in which a methoxy group iscleaved with boron tribromide. Preferred processes comprise reacting acompound of formula (4):

with an ether demethylating agent to produce a compound of formula (2):

In preferred processes, the ether demethylating agent is borontribromide (BBr₃). Those skilled in the art are familiar with additionalagents suitable for demethylating methyl ethers. Particularly preferredprocesses involve methyl ether cleavage, as depicted in Scheme 3, below.

In such processes, a solution of1-benzyl-2-(6-methoxy-naphthalen-2-yl)-3-pentyl-1H-indole in methylenechloride generally is treated with 0.75 equivalents of boron tribromidein methylene chloride at 0° C., the resulting mixture is slowly heatedto 25° C., and the reaction is quenched with a 5% solution of sodiumhydroxide in water. The organic and aqueous layers are separated, andthe organic layer is replaced with toluene. Heptane is added to thesolution and the product is crystallized at 0° C. to produce 85% to 90%of 6-(1-benzyl-3-pentyl-1H-indol-2-yl)-naphthalen-2-ol.

The reaction depicted in Scheme 3 can be performed using alternativesolvents, including chlorinated hydrocarbons, such as, for example,1,2-dichloroethane; and aromatic hydrocarbons, such as, for example,xylenes, alkylbenzenes, and alkyltoluenes. The reaction temperature inthe process depicted in Scheme 3 can be much as 10° C. to 50° C. higheror lower than that indicated in the description provided above,depending upon the particular solvent used in the reaction.

The invention additionally relates to processes that include couplingsubstituted methyltetrazole with a substituted naphthol. Preferredprocesses are those in which the substituted methyltetrazole is directlycoupled with the naphthol and the tetrazole is protected. Inparticularly preferred embodiments, the tetrazole is pyran-protected. Inpreferred embodiments, a compound of formula (2):

wherein

R₁-R₆ are as defined herein;

is reacted with a compound of formula (3):

wherein

X is a leaving group and R₇ and n are as defined herein;

and an inorganic or organic base to produce a compound of formula (1):

or a pharmaceutically acceptable salt thereof.

In preferred embodiments, the leaving group is a halogen or a sulfonate.In particularly preferred processes, the leaving group is chlorine andthe compound of formula (3) is 5-chloromethyl-1H-tetrazole (CMT). Incertain aspects of the invention, the 5-chloromethyl-1H-tetrazole (CMT)is protected with, for example, a dihydropyran. This can be effected,for example, by reacting 5-chloromethyl-1H-tetrazole (CMT) with3,4-dihydro-3H-pyran (DHP) and pyridinium p-toluene sulfonate (PPTS) toproduce tetrahydropyran (THP) protected 5-chloromethyl-1H-tetrazole(CMT).

In certain processes, the inorganic or organic base is an alkalinecarbonate, an alkaline earth metal carbonate, an alkaline hydroxide, analkaline earth metal hydroxide, an amine, a phosphine, or an anionexchange resin. In particularly preferred embodiments of the invention,the inorganic or organic base is an alkaline carbonate such as, forexample, lithium carbonate, potassium carbonate, cesium carbonate, orsodium carbonate.

In certain embodiments, the compound of formula (1) is a compound offormula (1a):

Preferred compounds of formula (1a) are those of formula (1b):

Particularly preferred processes according to the invention involvecoupling chloromethyltetrazole with a substituted naphthol, as depictedin Scheme 4, below.

Crystalline 6-(1-benzyl-3-pentyl-1H-indol-2-yl)-naphthalen-2-olpreferably is added to a solution of tetrahydropyran (THP)-protected5-chloromethyl-1H-tetrazole (CMT) in acetone. Cesium carbonate at 0° C.is then added to the mixture and the suspension is heated at a refluxtemperature for four hours. Acetone is exchanged with toluene and theresulting suspension is quenched with hydrochloric acid and washed withwater. The solution is treated with concentrated hydrochloric acid andmethanol at 20° C. Toluene, followed by water, is added to the solution.The aqueous and organic layers are separated and the organic layer iswashed with water. Crystallization at 20° C. yields 70% of1-benzyl-3-pentyl-2-[6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-yl]-1H-indole.

In certain embodiments of the invention, the1-benzyl-3-pentyl-2-[6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-yl]-1H-indoleis recrystallized, preferably with ethyl acetate and heptane. Inparticularly preferred embodiments, the1-benzyl-3-pentyl-2-[6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-yl]-1H-indoleis recrystallized by dissolving the compound in ethyl acetate and addingheptane to initiate crystallization. Additional heptane is then added,the suspension is stirred, and is then filtered. The resultant cake iswashed with a mixture of ethyl acetate and heptane and dried.

In one aspect, the invention provides multi-step processes for thepreparation of substituted naphthylindole derivatives that can be usedas plasminogen activator inhibitor-1 (PAI-1) inhibitors. Such processescomprise one or more of the forgoing steps of converting a compound offormula (6) to a compound of formula (5), converting a compound offormula (5) to a compound of formula (4), converting a compound offormula (4) to a compound of formula (2), and converting a compound offormula (2) to a compound of formula (1) or a pharmaceuticallyacceptable salt thereof.

One particularly preferred process for preparing substitutednaphthylindole derivatives that can be used as inhibitors of plasminogenactivator inhibitor-1 (PAI-1), is depicted in Scheme 5, below.

The following examples are illustrative of certain embodiments of theinvention and should not be considered to limit the scope of theinvention.

Example 1 PREPARATION OF 1-(6-METHOXY-NAPHTHALEN-2-YL)HEPTAN-1-ONE USINGHEXYLMAGNESIUM BROMIDE

A 2.0 M solution of hexylmagnesium bromide in THF (31 mL, 62 mmol) wascooled to 0° C. A solution of 2-methoxy-6-naphthaldehyde (10.0 g, 53.7mmoles) in toluene (71 mL) was added to the pre-cooled hexylmagnesiumbromide solution under an inert atmosphere over 10 minutes, whilemaintaining the temperature of the solution in the range of −2° C. to+2° C. The solution was stirred for 20 min at 0° C., treated with1-methyl-4-piperidone (MPP, 1.34 g, 11.8 mmoles, 0.22 mol-equiv.), andheated to 65° C. Additional MPP (103 g, 91.3 mmoles, 1.70 mol-equiv.)was added at 65° C. over 11 hours at the general rate of 0.15mol-equiv./h (9.1 g/h). The resulting solution was cooled and 10%hydrochloric acid (88.1 g, 0.242 moles) was added at a rate sufficientto maintain the temperature below 30° C. The emulsion was stirred for anadditional 10 minutes, the layers were separated, and the aqueous layerwas removed (pH 1). The organic layer was dried with magnesium sulfate(4 g), filtered, and concentrated in vacuo to yield 14.2 g (98%) of alight-yellow solid as the title compound with 97.8% ar. HPLC purity.

Example 2 PREPARATION OF 1-(6-METHOXY-NAPHTHALEN-2-YL)HEPTAN-1-ONE USINGHEXYLLITHIUM

A 2.3 M solution of hexyllithium in hexane (0.29 L, 0.67 moles) wascooled to −15° C. A solution of 2-methoxy-6-naphthaldehyde (104 g, 0.559moles) in toluene (0.60 L) was added to the pre-cooled hexyllithiumsolution under an inert atmosphere over 1.5 hours, while maintaining thetemperature in the range of −10° C. to −15° C. Magnesium sulfate (78.0g, 0.644 moles) was added to the resulting brown hazy solution, bringingthe temperature up to −5° C. After 15 minutes, MPP (14.0 g, 0.124 moles,0.22 mol-equiv.) was added to the solution over a period of less thantwo minutes, which changed the solution's color from brown to lightyellow and raised the solution's temperature to 4° C. The suspension washeated to 65° C. and additional MPP (119 g, 1.05 moles, 1.88 mol-equiv.)was added over 6.5 hours at the general rate of 0.29 mol-equiv./h (18.3g/h). The mixture was cooled and 10% hydrochloric acid (900 g, 2.47moles) was added at a rate sufficient to maintain the temperature below30° C. During the HCl addition the reaction mixture cleared, a viscousphase formed on the bottom of the solution, and both phases turned red.When about half the acid was added, the color of the solution changed tobright yellow (water layer pH 6). Once all the acid was added, themixture became a homogeneous emulsion. The emulsion was stirred for anadditional 30 minutes, the layers were separated, and the bottom layerwas drained (pH 1). The upper layer was washed with water (0.3 kg), thebottom aqueous layer was separated (pH 3), and the residual solution wasconcentrated in vacuo to 0.3 L. Octane (1.07 L) was added to theresulting solution, while maintaining the temperature of the solution at60° C., and the mixture was concentrated in vacuo to 0.75 L. Thesolution was cooled to −3° C. (crystallization starts at ca. 40° C.) andstirred for 30 minutes at that temperature. The resultant light yellowsuspension was filtered, dried in a nitrogen stream on a filter for 30minutes, and the solids were vacuumed at 50° C./50 mm Hg, which yielded117 g (77.5%) of the title compound as a light-yellow crystallinematerial with 97.9% ar. HPLC purity.

Example 3 PREPARATION OF1-BENZYL-2-(6-METHOXYNAPHTHALEN-2-YL)-3-PENTYL-1H-INDOLE

1-(6-methoxy-naphthalen-2-yl)heptan-1-one (0.176 kg, 0.651 moles) wasdissolved in anhydrous ethanol (1.56 L), 1-benzyl-1-phenylhydrazinehydrochloride (BPH, 0.168 kg, 0.716 moles) was added, a 37% aqueoussolution of hydrochloric acid (1.2 g, 12.2 mmoles) was added, and thereaction mixture was heated under reflux for 7 hours. Two portions ofBPH (8.4 g, 71.6 mmoles each) were added to the mixture at one hourintervals at 70° C. The temperature of the mixture returned to thereflux temperature after the first BPH addition. Heating was terminated,the reaction mixture was diluted with heptane (1.65 L) followed by water(0.62 kg), and the mixture was stirred for 30 minutes while maintainingthe temperature at 45° C. The addition of heptane resulted in theprecipitation of solids from the homogeneous organic phase, while theaddition of water brought the mixture to a biphasic state with layers inan approximate ratio of 1:1. The bottom layer was drained (pH 1) and theupper layer was washed with water (0.26 kg) while stirring the mixturefor 30 minutes. The bottom layer was again drained (pH 3) and the upperlayer was cooled to 12° C. in the reactor. All operations subsequent tothe quenching step were conducted at 45° C. to prevent premature productcrystallization. About 10 grams of the chilled solution were withdrawnfrom the reactor, subjected to low-temperature crystallization, andreturned to the chilled solution as a seeding suspension. The mixturewas kept at 12° C. for 30 minutes, cooled to −10° C. over two hours, andstirred at that temperature for 30 minutes. The suspension was filtered,the solids were dried in a nitrogen stream on a filter for 30 minutes,and the solids were vacuumed at 50° C./50 mm Hg to yield 221 g (78%) ofthe title compound as light-yellow prills with 99.45% ar. HPLC purity.

Example 4 PREPARATION OF1-BENZYL-2-(6-HYDROXYNAPHTHALEN-2-YL)-3-PENTYL-1H-INDOLE

1-benzyl-2-(6-methoxynaphthalen-2-yl)-3-pentyl-1H-indole (210.0 g, 0.484mol) was dissolved in methylene chloride (620 mL), the solution wascooled to 0° C., and 1.0 M boron tribromide in methylene chloride (363mL, 0.363 mole) was added to the solution over 30 minutes. The reactionmixture was stirred for twelve hours at 20° C. to 25° C., at which pointin time HPLC analysis indicated that no starting material was present.The solution was cooled to 0° C.-10° C. and a 5% aqueous sodiumhydroxide solution (462 mL, 0.605 mole) was added to the solution over30 minutes. The mixture was stirred for 30 minutes and the layers wereseparated. The organic layer was washed with 15% aqueous sodium chloride(170 mL) and passed through a silica gel pad (210 g). The pad was washedwith two 250 mL portions of methylene chloride. The combined filtratewas concentrated by atmospheric distillation to a volume of 500 mL,toluene (260 mL) was added, and distillation was resumed until thevolume reached 500 mL. The temperature increased to 75° C.-80° C. duringthe distillation. Heptane (1040 mL) was then added while maintaining thetemperature. The mixture was cooled to 55° C. over 50 min. Approximately10 grams of the solution were withdrawn from the reactor, subjected tolow-temperature crystallization, and returned to the solution as aseeding suspension at 55° C. Crystallization began at 43° C.-45° C. Thesuspension was cooled to 0° C.-5° C. and stirred at that temperature fortwo hours. The solid was filtered, washed with 500 mL heptane, and driedat 50° C./50 torr for 24 hours to produce 166.0 g (81.7% yield) of thetitle compound as an off-white solid with 99.89% ar. HPLC purity.

Example 5 PREPARATION OF1-BENZYL-3-PENTYL-2-[6-(1H-TETRAZOL-5-YLMETHOXY)NAPHTHALEN-2-YL]-1H-INDOLE

Pyridinium p-toluenesulfonate (0.16 kg, 0.64 mol) was added to asolution of 5-chloromethyl-1H-tetrazole (2.37 kg, 20.0 mol) and3,4-dihydro-3H-pyran (2.83 kg, 33.6 mol) in acetone (20 L) and theresultant solution was heated at 45° C. for 3 hours. Additional3,4-dihydro-3H-pyran (1.46 kg, 17.4 mol) was added and heating wascontinued for 2 hours.1-benzyl-2-(6-hydroxynaphthalen-2-yl)-3-pentyl-1H-indole (7.0 kg, 16.7mol) was added and the solution was stirred at 17° C. Cesium carbonate(6.77 kg, 20.8 mol) was then added. The temperature of the suspensionwas adjusted to 60° C. and heating was continued for 3 hours, at whichtime HPLC analysis showed 100% conversion. Toluene (55 L) was added andacetone was removed by atmospheric distillation. The mixture was heatedto 100° C. to provide 35 L of residual volume. After cooling the residueto 20° C., a solution of 1 N hydrochloric acid (28.6 L) was added, themixture was stirred for 30 minutes, and the layers were separated. Theupper organic layer was treated with a mixture of concentratedhydrochloric acid (8.3 kg, 84.2 mol) and methanol (28 L) at 20° C. for30 minutes, the time necessary to complete hydrolysis, followed bydilution with toluene (58 L). A 1 N sodium hydroxide solution (35 L) wasadded, which changed the pH to 4. The layers were separated and theupper organic layer was washed with a 17% sodium chloride solution (35L) at 40° C. The toluene layer was slowly cooled to −3° C.(crystallization begins at 21° C.) while being stirred for 1 hour. Thesuspension was then filtered, and the cake was washed with cold toluene(−3° C., 40 L) to yield, after drying, 6.4 kg (76.4% yield) of the titlecompound as an off-white solid with 99.26% ar. HPLC purity.

Example 6 RE-CRYSTALLIZATION OF1-BENZYL-3-PENTYL-2-[6-(1H-TETRAZOL-5-YLMETHOXY)NAPHTHA-LEN-2-YL]-1H-INDOLE

Crude1-benzyl-3-pentyl-2-[6-(1H-tetrazol-5-ylmethoxy)naphtha-len-2-yl]-1H-indole(6.4 kg) was dissolved in ethyl acetate (22 L) at 38° C., the solutionwas cooled to 22° C., and the solution was passed through a 10-μm filtercartridge. Heptane (20 L) was added to the resultant solution at 23° C.to initiate crystallization. As soon crystallization began, more heptane(28 L) was added, the suspension was stirred for 19 hours, and thesuspension was then filtered on a Nutsche filter. The cake was washedwith a mixture of ethyl acetate (6.4 L) and heptane (13.2 L) and driedin the filter using a nitrogen stream for 18 hours, to provide 4.4 kg(68.8%) of the title API with 99.76% ar. HPLC purity, 0.019% of residualheptane and no detectable ethyl acetate or toluene.

The entire disclosure of each patent, patent application, andpublication cited or described in this document is hereby incorporatedherein by reference.

1. A process comprising reacting a compound of formula (6):

wherein R₃, and R₄ are each, independently, hydrogen, alkyl of 1 to 3carbon atoms, cycloalkyl of 3 to 5 carbon atoms, —CH₂cycloalkyl of 4 to6 carbon atoms, alkanoyl of 2 to 4 carbon atoms, halogen, hydroxyl, arylof 6 to 14 carbon atoms optionally substituted with 1 to 3 R₈ groups,perfluoroalkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms,amino, alkylamino of 1 to 3 carbon atoms, dialkylamino of 1 to 3 carbonatoms, or perfluoroalkoxy of 1 to 3 carbon atoms; and R₈ is hydrogen,alkyl of 1 to 3 carbon atoms, cycloalkyl of 3 to 5 carbon atoms,—CH₂cycloalkyl of 4 to 6 carbon atoms, alkanoyl of 2 to 4 carbon atoms,halogen, hydroxy, perfluoroalkyl of 1 to 3 carbon atoms, alkoxy of 1 to3 carbon atoms, amino, alkylamino of 1 to 3 carbon atoms, dialkylaminoof 1 to 3 carbon atoms, or perfluoroalkoxy of 1 to 3 carbon atoms; withan alkylmagnesium halide or an arylmagnesium halide having the formulaR₉MgBr and further with a hydride acceptor to produce a compound offormula (5):

wherein R₉ is —CH₂—R₅; or reacting a compound of formula (6)consecutively with an alkyllithium having the formula R₉Li, a magnesiumsalt, and a hydride acceptor to produce a compound of formula (5). 2.The process of claim 1 wherein the alkylmagnesium halide ishexylmagnesium bromide (HxMgBr).
 3. The process of claim 1 wherein thealkyllithium is hexyllithium.
 4. The process of claim 1 wherein themagnesium salt is magnesium bromide, magnesium chloride, a magnesiumsulfonate, or magnesium sulfate.
 5. The process of claim 1 wherein thehydride acceptor is an optionally substituted dialkylaminobenzaldehydeor an optionally substituted aminocycloalkanone.
 6. The process of claim5 wherein the hydride acceptor is 1-methyl-4-piperidone (MPP).
 7. Theprocess of claim 1 wherein the compound of formula (5) is produced by aprocess comprising reacting a compound of formula (6) with analkylmagnesium halide or an arylmagnesium halide having the formulaR₉MgBr and further with a hydride acceptor.
 8. The process of claim 1further comprising reacting a compound of formula (5) with a substitutedhydrazine having the formula

to produce a compound of formula (4):

wherein R₁, and R₂ are each, independently, hydrogen, alkyl of 1 to 3carbon atoms, cycloalkyl of 3 to 5 carbon atoms, —CH₂cycloalkyl of 4 to6 carbon atoms, alkanoyl of 2 to 4 carbon atoms, halogen, hydroxyl, arylof 6 to 14 carbon atoms optionally substituted with 1 to 3 R₈ groups,perfluoroalkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms,amino, alkylamino of 1 to 3 carbon atoms, dialkylamino of 1 to 3 carbonatoms, or perfluoroalkoxy of 1 to 3 carbon atoms; R₅ is hydrogen, alkylof 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, aryl of 6to 14 carbon atoms optionally substituted with 1 to 3 R₈ groups,alkanoyl of 2 to 7 carbon atoms, or aroyl of 7 to 15 carbon atomsoptionally substituted with 1 to 3 R₈ groups; and R₆ is hydrogen, alkylof 1 to 6 carbon atoms, alkylaryl of 8 to 20 carbon atoms, benzyloptionally substituted with 1 to 3 R₈ groups, alkanoyl of 2 to 7 carbonatoms, or aroyl of 7 to 15 carbon atoms optionally substituted with 1 to3 R₈ groups.
 9. The process of claim 8 wherein the substituted hydrazineis 1-benzyl-1-phenylhydrazine hydrochloride (BPH).
 10. The process ofclaim 8 further comprising reacting a compound of formula (4) with anether demethylating agent to produce a compound of formula (2):


11. The process of claim 10 wherein the ether demethylating agent isboron tribromide (BBr₃).
 12. The process of claim 10 further comprisingreacting a compound of formula (2) with a compound of formula (3):

wherein X is a leaving group; R₇ is hydrogen, alkyl of 1 to 6 carbonatoms, alkylaryl of 7 to 20 carbon atoms, or aryl of 6 to 14 carbonatoms optionally substituted with 1 to 3 R₈ groups; and n is an integerfrom 0 to 6; and an inorganic or organic base to produce a compound offormula (1):

or a pharmaceutically acceptable salt thereof.
 13. The process of claim12 wherein X is a halogen or a sulfonate.
 14. The process of claim 12wherein the compound of formula (3) is 5-chloromethyl-1H-tetrazole(CMT).
 15. The process of claim 14 further comprising reacting the5-chloromethyl-1H-tetrazole (CMT) with 3,4-dihydro-3H-pyran (DHP) andpyridinium p-toluene sulfonate (PPTS) to produce tetrahydropyran (THP)protected 5-chloromethyl-1H-tetrazole (CMT) prior to reaction with thecompound of formula (2).
 16. The process of claim 12 wherein theinorganic or organic base is an alkaline carbonate, an alkaline earthmetal carbonate, an alkaline hydroxide, an alkaline earth metalhydroxide, an amine, a phosphine, or an anion exchange resin.
 17. Theprocess of claim 16 wherein the alkaline carbonate is lithium carbonate,potassium carbonate, cesium carbonate, or sodium carbonate.
 18. Aprocess comprising (a) reacting a compound of formula (6):

wherein R₃, and R₄ are each, independently, hydrogen, alkyl of 1 to 3carbon atoms, cycloalkyl of 3 to 5 carbon atoms, —CH₂cycloalkyl of 4 to6 carbon atoms, alkanoyl of 2 to 4 carbon atoms, halogen, hydroxyl, arylof 6 to 14 carbon atoms optionally substituted with 1 to 3 R₈ groups,perfluoroalkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms,amino, alkylamino of 1 to 3 carbon atoms, dialkylamino of 1 to 3 carbonatoms, or perfluoroalkoxy of 1 to 3 carbon atoms; and R₈ is hydrogen,alkyl of 1 to 3 carbon atoms, cycloalkyl of 3 to 5 carbon atoms,—CH₂cycloalkyl of 4 to 6 carbon atoms, alkanoyl of 2 to 4 carbon atoms,halogen, hydroxy, perfluoroalkyl of 1 to 3 carbon atoms, alkoxy of 1 to3 carbon atoms, amino, alkylamino of 1 to 3 carbon atoms, dialkylaminoof 1 to 3 carbon atoms, or perfluoroalkoxy of 1 to 3 carbon atoms; withn-hexylmagnesium bromide (HxMgBr) and further with 1-methyl-4-piperidone(MPP) to produce a compound of formula (5):

wherein R₉ is n-hexyl; or reacting a compound of formula (6)consecutively with n-hexyllithium, magnesium sulfate, and1-methyl-4-piperidone (MPP) to produce a compound of formula (5) whereinR₉ is n-hexyl; (b) reacting a compound of formula (5) with1-benzyl-1-phenyl hydrazine hydrochloride (BPH) to produce a compound offormula (4):

wherein R₁ and R₂ are each hydrogen R₅ is n-pentyl; and R₆ is benzyl;(c) reacting a compound of formula (4) with boron tribromide (BBr₃) toproduce a compound of formula (2):

and (d) reacting a compound of formula (2) with5-chloromethyl-1H-tetrazole (CMT) and cesium carbonate to produce acompound of formula (1):

wherein n is 0 and R₇ is hydrogen; or a pharmaceutically acceptable saltthereof.
 19. The process of claim 18 further comprising reacting the5-chloromethyl-1H-tetrazole (CMT) with 3,4-dihydro-3H-pyran (DHP) andpyridinium p-toluene sulfonate (PPTS) to produce tetrahydropyran (THP)protected 5-chloromethyl-1H-tetrazole (CMT) prior to reaction with thecompound of formula (2).
 20. The process of claim 18 wherein thecompound of formula (5) is produced by the process comprising reacting acompound of formula (6) with hexylmagnesium bromide (HxMgBr) and furtherwith 1-methyl-4-piperidone (MPP).
 21. The process of claim 18 whereinthe compound of formula (1) is a compound of formula (1a):

wherein R_(1a), R_(3a), and R_(4a) are each, independently, hydrogen,alkyl of 1 to 3 carbon atoms, cycloalkyl of 3 to 5 carbon atoms,alkanoyl of 2 to 4 carbon atoms, halogen, hydroxyl, aryl of 6 to 14carbon atoms optionally substituted with 1 to 3 R₈ groups,perfluoroalkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms,amino, alkylamino of 1 to 3 carbon atoms, dialkylamino of 1 to 3 carbonatoms, or perfluoroalkoxy of 1 to 3 carbon atoms.
 22. The process ofclaim 21 wherein the compound of formula (1a) is a compound of formula(1b):